Open Access
Muelly, Emilie Ruth
Graduate Program:
Doctor of Philosophy
Document Type:
Date of Defense:
June 14, 2011
Committee Members:
  • Scott C Bunce, Dissertation Advisor/Co-Advisor
  • Ian Alexander Simpson, Committee Chair/Co-Chair
  • Scott C Bunce, Committee Member
  • James Robert Connor, Committee Member
  • Qing X Yang, Committee Member
  • Gregory Thomas Moore, Committee Member
  • Julie A Mack, Committee Member
  • branched chain amino acids
  • leucine
  • glutamate
  • metabolism
  • inborn errors of metabolism
  • metabolic disorders
  • neuroimaging
  • magnetic resonance spectroscopy
  • magnetic resonance imaging
  • MRI
  • MSUD maple syrup urine disease
  • psychiatry
  • IQ
  • intelligence quotient
  • mental retardation
  • depression
  • anxiety
  • ADHD
  • attention deficit and hyperactivity disorder
Maple Syrup Urine Disease (MSUD) is a rare, inherited metabolic deficiency common in the Old Order Mennonites of central Pennsylvania. Impaired branched-chain &#945;-keto acid dehydrogenase in MSUD patients leads to the accumulation of branched chain amino acids leucine, isoleucine, and valine, as well as their respective keto acids. Buildup of these molecules causes neurotoxicity if left untreated. Although dietary treatments limiting amino acid intake are effective, patients are still at risk for episodic metabolic intoxication and impaired intellectual outcomes. Anecdotal reports have suggested an increased prevalence of attention deficit disorder, depression, and anxiety, but these symptoms have not been formally investigated or quantitatively described. Neuropathology reports, animal models, and in vitro studies suggest two potential mechanisms by which the underlying defect in MSUD may lead to acute neural sequelae: energy deprivation and neurotransmitter depletion. It is possible that these mechanisms also impact chronic sequelae. This research provides a unique neuropsychiatric and neurochemical profile of medically managed MSUD patients free of acute illness, offering insights into the mechanisms of chronic sequelae. Liver transplantation has recently emerged as a treatment option for MSUD patients, as the transplanted liver contains sufficient branched-chain &#945;-keto acid dehydrogenase to prevent extreme, rapid increases in plasma branched chain amino and keto acids. Liver transplantation has been shown to prevent acute neurotoxicity during acute illness; however, its effect on chronic sequelae is unknown. This research provides preliminary data on neuropsychiatric symptoms and neurochemistry in MSUD patients who have undergone liver transplant therapy. Twenty-six MSUD patients metabolically controlled with dietary therapy and twenty-six unaffected family member controls participated in the study. Prevalence of neuropsychiatric conditions was assessed using the Wechsler Abbreviated Scale of Intelligence and Structured Clinical Interview for the DSM-IV. Additionally, symptoms were characterized using continuous scales of attention, depression, and anxiety. Neurochemistry was quantified in three regions of interest: the medial prefrontal cortex and adjacent anterior cingulate gray matter (PFC+ACC), the left basal ganglia, and the right parietal white matter. Linear combination modeling was used to quantify metabolites, which were then compared between subject groups and correlated with continuous measures of neuropsychiatric outcomes. To begin to evaluate the effects of liver transplantation on chronic sequelae of MSUD, 11 MSUD patients who had undergone liver transplantation therapy were also evaluated with the above measures. Confirming anecdotal clinical observations, MSUD patients were found to have a higher prevalence of neuropsychiatric conditions relative to controls. Average IQ scores were twenty-five points lower in the MSUD population (p < 0.001), although some patients exhibited normal intelligence. MSUD patients were twice as likely as controls to meet diagnostic criteria for ADHD at the time of evaluation (p = 0.04), seven times as likely to meet criteria for a current depressive disorder (p = 0.02), and more than twice as likely to meet criteria for a current anxiety disorder (p = 0.06). Neurochemical abnormalities were also observed in MSUD patients. Most notably, patients had lower glutamate concentrations in all three brain regions (p < 0.001), and region-specific deficits in energy molecules N-acetylaspartate (NAA) and creatine. Neurochemistry correlated with neuropsychiatric outcomes. Increased NAA in the basal ganglia corresponded with increased non-verbal IQ scores in MSUD subjects. Depression and anxiety ratings corresponded with decreases in glutamate and NAA in the ACC + PFC and attention impairments corresponded with multiple biochemical alterations in both basal ganglia and PFC + ACC. MSUD subjects who received a liver transplant varied in both the age at which they had received the transplant (range: 2.2 -22.4 years) and the length of time since liver transplantation (range: 0.2 – 14.0 years). Transplanted subjects did not statistically differ from MSUD patients in terms of neuropsychiatric symptoms or neurochemical profiles. Our findings support the hypothesis that altered neurochemical pathways in the non-acute state of MSUD contribute to chronic impairments in neuronal mitochondrial function and neurotransmitter metabolism, which may contribute to neuropsychiatric symptoms. Altered neurochemistry in the basal ganglia appears to correspond primarily with outcomes related to psychomotor retardation, while functions of emotion regulation and attention were more related to differences in the PFC + ACC region. Our data in transplant patients suggest that liver transplantation, although highly effective for eliminating risk of acute crises, does not significantly impact chronic sequelae.